Alternative titles; symbols
HGNC Approved Gene Symbol: NOP10
Cytogenetic location: 15q14 Genomic coordinates (GRCh38): 15:34,341,719-34,343,136 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q14 | ?Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 2 | 620425 | Autosomal recessive | 3 |
| ?Dyskeratosis congenita, autosomal recessive 1 | 224230 | Autosomal recessive | 3 | |
| ?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9 | 620400 | Autosomal dominant | 3 |
By searching an EST database for orthologs of yeast Nop10, Henras et al. (1998) identified an EST encoding a protein 60% identical to the yeast protein. By EST database searching followed by 5-prime and 3-prime RACE, Pogacic et al. (2000) obtained a cDNA encoding NOP10, which they called NOP10. The deduced 64-amino acid protein could replace the yeast protein in complementation assays. Pogacic et al. (2000) noted that NOP10 is conserved in eukaryotes and archaea, but no similar sequence could be identified in bacteria.
Using immunoprecipitation studies and Western blot analysis, Pogacic et al. (2000) found that NOP10 associates with NHP2 (NOLA2; 606470), dyskerin (DKC1; 300126), and GAR1 (NOLA1; 606468) in structures corresponding to H/ACA small nucleolar RNPs (snoRNPs), but not to C/D snoRNPs, and to telomerase. SnoRNPs of the H/ACA class specify the sites of uridine-to-pseudouridine conversion (see Tollervey and Kiss, 1997). Immunofluorescence microscopy demonstrated colocalization of NOP10 with NOLA1, NOLA2, and DKC1, but not with fibrillarin (FBL; 134795), in nucleolar dense fibrillar components and in Cajal bodies (also called coiled bodies; see 600272).
Walne et al. (2007) demonstrated that knockdown of NOP10 expression in HeLa cells by siRNA resulted in reduction in the amount of telomerase RNA component (TERC; 602322).
Gross (2021) mapped the NOP10 gene to chromosome 15q14 based on an alignment of the NOP10 sequence (GenBank BC008886) with the genomic sequence (GRCh38).
Autosomal Recessive Dyskeratosis Congenita 1
In all 3 affected members of a Saudi family with autosomal recessive dyskeratosis congenita-1 (DKCB1; 224230), Walne et al. (2007) identified a homozygous mutation in the NOP10 gene (606471.0001). Those affected had significant telomere shortening and reduced TERC levels.
Telomere-Related Pulmonary Fibrosis And/Or Bone Marrow Failure Syndrome 9
In 4 affected individuals from a large family with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-9 (PFBMFT9; 620400), Kannengiesser et al. (2020) identified a heterozygous missense mutation in the NOP10 gene (Y6C; 606471.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 140,000 individuals in the gnomAD database. One unaffected family member also carried the mutation, suggesting incomplete penetrance. Functional studies of the mutation and studies of patient cells were not performed, but molecular modeling demonstrated that the affected residue is in a region in close contact with DKC1 (300126) and likely disrupts stability of the domain and the NOP10 complex. Patients with the mutation showed short telomeres, although 1 noncarrier also had short telomeres, suggesting that epigenetic factors may play a role in telomere length.
Cataracts, Hearing Impairment, Nephrotic Syndrome, And Enterocolitis 2
In 2 girls from a highly consanguineous family (family B) with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-2 (CHINE2; 620425), Balogh et al. (2020) identified a homozygous missense mutation in the NOP10 gene (T16M; 606471.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not present in the general population. The mutation occurred in the DKC1 (300126)-NOP10 interface in a region distinct from those implicated in dyskeratosis congenita. Although the binding interaction with DKC1 was maintained, molecular modeling and in vitro studies showed that the T16M mutation altered the hydrogen binding between NOP10 and DKC1, disrupted the catalytic pseudouridylation site, and altered the pseudouridylation capacity of the snoRNP complex. Peripheral blood cells from 1 of the patients showed a pseudouridylation defect of 18S rRNA. Despite the finding of shortened telomeres in the affected females, the authors concluded that a pseudouridylation defect causing ribosomal dysfunction is the primary driver of this unique phenotype.
In 3 affected members of a consanguineous Saudi family with autosomal recessive dyskeratosis congenita-1 (DKCB1; 224230), Walne et al. (2007) identified homozygosity for a c.100C-T transition in exon 2 of the NOP10 gene, resulting in an arg34-to-trp substitution. The mutation occurs in a highly conserved region of the protein and is predicted to change the structure of the protein. Unaffected family members were heterozygous for the mutation, which was not present in 56 ethnically matched healthy individuals.
In 4 affected individuals from a large family with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-9 (PFBMFT9; 620400), Kannengiesser et al. (2020) identified a heterozygous c.17A-G transition (c.17A-G, NM_018648) in the NOP10 gene, resulting in a tyr6-to-cys (Y6C) substitution at a conserved residue in the small N-terminal globular ribbon domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 140,000 individuals in the gnomAD database. One unaffected family member also carried the mutation, suggesting incomplete penetrance. Functional studies of the mutation and studies of patient cells were not performed, but molecular modeling demonstrated that the affected residue is in a region in close contact with DKC1 (300126) and likely disrupts stability of the domain and the NOP10 complex. Patients with the mutation showed short telomeres, although 1 noncarrier also had short telomeres, suggesting that epigenetic factors may play a role in telomere length.
In 2 girls from a highly consanguineous family (family B) with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-2 (CHINE2; 620425), Balogh et al. (2020) identified a homozygous c.47C-T transition in the NOP10 gene, resulting in a thr16-to-met (T16M) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not present in the general population. The mother of one of the affected girls had hearing impairment, but her genotype was not noted. Patient cells showed a reduced level of the mutant NOP10 protein, suggesting a possible effect on protein stability. The mutation occurred in the DKC1 (300126)-NOP10 interface in a region distinct from those implicated in dyskeratosis congenita. Although the binding interaction with DKC1 was maintained, molecular modeling and in vitro studies showed that the T16M mutation altered the hydrogen binding between NOP10 and DKC1, disrupted the catalytic pseudouridylation site, and altered the pseudouridylation capacity of the snoRNP complex. Peripheral blood cells from 1 of the patients showed a pseudouridylation defect of 18S rRNA. Despite the finding of shortened telomeres in the affected females, the authors concluded that a pseudouridylation defect causing ribosomal dysfunction is the primary driver of this unique phenotype.
Balogh, E., Chandler, J. C., Varga, M., Tahoun, M., Menyhard, D. K., Schay, G., Goncalves, T., Hamar, R., Legradi, R., Szekeres, A., Gribouval, O., Kleta, R., and 45 others. Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis. Proc. Nat. Acad. Sci. 117: 15137-15147, 2020. [PubMed: 32554502] [Full Text: https://doi.org/10.1073/pnas.2002328117]
Gross, M. B. Personal Communication. Baltimore, Md. 11/1/2021.
Henras, A., Henry, Y., Bousquet-Atonelli, C., Noaillac-Depeyre, J., Gelugne, J.-P., Caizergues-Ferrer, M. Nhp2p and Nop10p are essential for the function of H/ACA snoRNPs. EMBO J. 17: 7078-7090, 1998. [PubMed: 9843512] [Full Text: https://doi.org/10.1093/emboj/17.23.7078]
Kannengiesser, C., Manali, E. D., Revy, P., Callebaut, I., Ba, I., Borgel, A., Oudin, C., Haritou, A., Kolilekas, L., Malagari, K., Borie, R., Lainey, E., Boileau, C., Crestani, B., Papiris, S. A. First heterozygous NOP10 mutation in familial pulmonary fibrosis. Europ. Resp. J. 55: 1902465, 2020. [PubMed: 32139460] [Full Text: https://doi.org/10.1183/13993003.02465-2019]
Pogacic, V., Dragon, F., Filipowicz, W. Human H/ACA small nucleolar RNPs and telomerase share evolutionarily conserved proteins NHP2 and NOP10. Molec. Cell. Biol. 20: 9028-9040, 2000. [PubMed: 11074001] [Full Text: https://doi.org/10.1128/MCB.20.23.9028-9040.2000]
Tollervey, D., Kiss, T. Function and synthesis of small nucleolar RNAs. Curr. Opin. Cell Biol. 9: 337-342, 1997. [PubMed: 9159079] [Full Text: https://doi.org/10.1016/s0955-0674(97)80005-1]
Walne, A. J., Vulliamy, T., Marrone, A., Beswick, R., Kirwan, M., Masunari, Y., Al Qurashi, F., Aljurf, M., Dokal, I. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum. Molec. Genet. 16: 1619-1629, 2007. [PubMed: 17507419] [Full Text: https://doi.org/10.1093/hmg/ddm111]